Gastrointestinal Metastases From Lobular Breast Carcinoma: A Literature Review

Invasive lobular carcinoma (ILC) represents a rare subtype of breast carcinoma, originating from the lobule. Unlike ductal carcinoma, ILC does not express E-cadherin and thus can metastasize to uncommon sites. We aimed to investigate the clinicopathological characteristics of the rare subgroup of ILC patients with gastrointestinal (GI) metastases. A PubMed search was undertaken using the terms “Lobular Breast Carcinoma” AND “Gastrointestinal Metastasis.” We identified 169 cases, with metachronous GI metastatic disease being approximately twice as common as synchronous GI metastases. The median age at initial diagnosis was 56.7 years (24-88). The majority of patients were hormonal receptor-positive and only a small minority was HER2-positive. The appearance of a gastrointestinal lesion was often the mode of revelation of ILC. Differential diagnosis from primary gastrointestinal cancer is sometimes challenging, especially in the case of signet-ring cell carcinoma. The median time from breast cancer diagnosis to GI metastases was 6.5 years (0-33). Most common metastatic sites include the stomach, colon, and rectum, in order of decreasing frequency, whereas metastases were found in every part of the digestive tract. In conclusion, metastases of ILC can arise in the gastrointestinal tract and they should be managed similarly to metastatic breast cancer.


Introduction And Background
Invasive lobular carcinoma (ILC) of the breast is the second most common type of invasive breast carcinoma which accounts for approximately 10% of all breast cancers [1], with an increasing incidence, especially among postmenopausal females [2].Histopathologic pattern of ILC differs from invasive ductal carcinoma (IDC) and is characterized by small round cells infiltrating the stroma of the breast as individual rows (single or Indian file) [3].This type of infiltration generally does not disrupt anatomical structures and does not induce any substantial conjunctive tissue response.Therefore, ILC often does not form a distinct mass in the breast and diagnosis can be challenging by palpation or mammography [4].It has a tendency for a multifocal, multicentric, and bilateral distribution [5,6].There are several histopathological variants, including classic, solid, alveolar, tubuloglobular, pleomorphic, and mixed.Notably, the pleomorphic variant may show apocrine or histiocytoid differentiation and may be composed of signet ring cells [7].
ILC has almost invariably positive hormone receptors and HER2 positivity is very rare, generally limited to the pleomorphic variant.In addition, E-cadherin is usually absent or reduced in ILC but 10-16% of ILC may express E-cadherin with unknown prognostic significance [8].It is suggested that ILC has a higher rate of distant metastases, in comparison to IDC, probably due to its infiltrative nature [9,10].It is known that loss of E-cadherin, the molecule of intercellular adhesion, may facilitate the metastatic process.Similarly to the breast, metastatic ILC tends to infiltrate the affected organs in a diffuse pattern, instead of forming a welldefined tumoral nodule.
Interestingly, ILC patterns of metastasis differ significantly from IDC. Distinctive metastatic sites of ILC include intraabdominal serosal surfaces, gastrointestinal tract, genitourinary system organs, and leptomeninges, whereas pulmonary metastases are less frequent, for unknown reasons, while the most common sites of metastasis of IDC involve the bone, liver, and lungs [4,9,11,12].Gastrointestinal metastasis (GI) of ILC constitutes a clinical challenge for physicians since primary gastrointestinal malignancy is considered a differential diagnosis.
We collected histopathological information on both the primary breast tumor and gastrointestinal metastasis, including biomarkers estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2).ER and PR were classified as positive or negative, according to the conclusion of each laboratory.In the case of HER2 score of 2+, we searched for fluorescence in situ hybridization (FISH) or chromogenic in situ hybridization (CISH) results.Clinical information was also registered concerning the stage at first diagnosis and the initial management of breast tumors in case of metachronous metastases.
The exact locations of both gastrointestinal and other metastases were registered.We analyzed separately the symptoms and signs associated with gastrointestinal metastases, as well as their treatment (local or other) and prognosis.
This study represents a narrative synthesis of the available literature.Tables are used to summarize the characteristics and findings of the included studies.For this qualitative study, we used simple descriptive statistics methods.Only cases with available data were included in the statistical analysis and different percentages refer to this population.For time-to-event analysis, the Kaplan-Meier method was used.Statistical analyses were computed using SPSS version 28 (Armonk, NY: IBM Corp.).

Results
A total of 169 cases were incorporated into this analysis, including 85 case reports and six case series (Table 1) .Three out of the six case series, including 64 patients in total, represent pooled analyses of cases and do not contain any individual clinical and histological information [93,96,97].Age at initial diagnosis (of either primary breast cancer or metastatic disease) varied between 24 and 88 years, with a median value of 56.7.All patients were females.Among cases with known ER status (n=76), 90.8% (n=69) of mammary tumors were positive.Among cases with known PR status (n=68), 75% (n=51) of mammary tumors were positive.Among cases with known HER2 status (n=65), 93.8% (n=61) were negative, 4.6% (n=3) positive, and 1.5% (n=1) equivocal (Table 1).There are also five patients with triple-negative breast carcinoma [17,35,41,73,76].All breast tumors were lobular carcinomas, apart from eight cases with mixed ductal and lobular histology [22,43,85,93,97].

Case
For 109 patients the initial stage of diagnosis was available.Among them, in almost one female out of three (33%) initial diagnosis was made at stage IV.In the majority of these cases, gastrointestinal metastasis was the mode of revelation of breast carcinoma.For the rest of the patients, primary breast cancer preceded the diagnosis of gastrointestinal metastases.For less than half of the patients of the latter group exact stage is available, with the majority diagnosed with stage III disease (n=16).
All primary breast tumors were treated with surgery and eight additional metastatic patients also underwent breast surgery.Among the 99 cases with available information on surgery, 50 (50.5%)underwent mastectomy, 10 (10.1%) lumpectomy, seven (7.1%) breast surgery with no further information, and 31 (31.3%) did not receive any surgery due to stage IV disease.In most patients, (sentinel) lymph node dissection was also performed.Of the 73 patients with stage I-III disease at diagnosis, 29 (39.7%) received adjuvant chemotherapy, mainly taxanes and anthracyclines, 10 (13.7%) did not receive chemotherapy, and the information was not available for the remaining patients.Forty-one patients received adjuvant radiation therapy (RT) to the breast, 25 of them had early breast cancer, five had stage IV disease, and in 11 cases the stage at the time of RT was not mentioned.Adjuvant hormonal therapy was reported in 34 patients, six of whom received aromatase inhibitors (AI), eight tamoxifen, five with tamoxifen switched to AI, and for 15 patients the type of hormonal therapy is not known.
Time from initial diagnosis to metastases varies between 0 and 33 years, with a median value of five years (95% CI: 4.23-5.77).In the majority of cases, histological diagnosis of metastasis was similar to breast tumor, except for six diagnoses of poorly differentiated carcinoma [15,16,20,26,33] and one of epithelioid neoplasm [19].Similarly, receptor status does not vary significantly between primary breast carcinoma and GI metastasis, with 86.3% ER-positive (n=82), 55.4% PR-positive (n=36), and 81.6% (n=40) HER2-negative metastatic tumors, among patients with available information on receptors status (Table 2).Six additional GI metastases were HER2-positive and two HER2-low (     Systemic treatment refers to chemotherapy or hormonal treatment given after gastrointestinal metastasis diagnosis.When there are no further details on the type of hormonal treatment or chemotherapy administered, "chemo" or "hormonal" is reported in the column "systemic treatment," respectively.Transverse and sigmoid refer to the colon.Survival after GI metastasis is expressed in years Concerning hormonal treatment for GI metastases, aromatase inhibitors (letrozole, anastrozole) were mostly used, whereas selective estrogen receptor modulators (tamoxifen and toremifene) were also administered to some patients.In addition, fulvestrant alone or in combination with everolimus was also given to three patients [24,38,47].In the most recent reports, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, combined with AI or fulvestrant, were frequently chosen.Given that the hormonal agents were not always reported, we did not calculate the exact frequency of each drug.
Most common chemotherapy regimens included taxanes and anthracyclines, in line with advanced breast cancer guidelines.Other drugs were also used, such as capecitabine, carboplatin, vinorelbine, and eribulin.Two patients received the monoclonal antibody bevacizumab in combination with chemotherapy [28,39].Two patients received anti-HER2 treatment (trastuzumab) without concomitant chemotherapy [22,23].
Only four patients were treated with radiation therapy delivered to GI metastases, two of which to the rectum [18,40], one to the anus [50] and one to the stomach [37].The latter was considered initially as a primary gastric tumor, and concomitant radiotherapy with chemotherapy was chosen.
Finally, 40 patients (40.4%) underwent a kind of intervention, more or less invasive, for their GI metastasis, 59 patients (59.6%) did not, whereas for the remaining 71 patients the information was not available (Table 3).Several patients underwent emergent surgery for intestinal obstruction, including small bowel resection (n=5) and colostomy (n=8).More sophisticated surgeries were performed on patients with gastrointestinal tumors initially considered primary, including the Whipple procedure (n=2), gastrectomy (n=5), colectomy (n=9), and abdominoperineal resection (n=1).Another four patients required an esophageal stent.
Survival data was not available for the whole population; therefore, we analyzed only a limited number of cases.Median survival since diagnosis of GI metastasis is seven years (one month to 13.3 years, 95% CI: 2.9-11.1).We did not perform any subgroup analysis to identify potential associations of survival with metastatic sites or different treatments, given the small sample size.

Discussion
This review represents an analysis of the 169 reported cases of gastrointestinal metastases from lobular breast carcinoma, in terms of histological characteristics of both primary tumors and metastases, different treatments, and outcomes.The majority of cases were HR-positive, HER2-negative luminal carcinoma, as expected for luminal breast carcinoma.Our analysis was limited to lobular carcinoma, as they are more likely to metastasize to the GI tract [99].A large retrospective series of 4140 patients demonstrated that IDC has a probability of 1.1% of GI metastasis, versus 4.5% in ILC [4].
One possible explanation is the loss of E-cadherin expression in ILC.Epithelial cadherin or E-cadherin belongs to a class of trans-membranous proteins and is critical in tumor progression, functioning as suppressor of invasion and metastasis in numerous contexts.They play a crucial role in cell-to-cell contact formation and stability, as they mediate cell-cell adhesion within tissues.Their function depends on calcium ions, which is the root of their names [100].
It should be noted that most patients with metachronous GI metastases were initially diagnosed with stage III disease.However, four patients presented with metastases eight to 10 years after stage I breast carcinoma diagnosis [14,40,41,63].
Metastases of the GI tract are rare in general.Breast cancer and in particular ILC is one of the most common primary tumors able to metastasize to this location.Furthermore, melanoma, lung cancer, renal cancer, ovarian cancer, and pancreatic cancer have also been associated with secondary GI localizations [101,102].
In the case of GI lesion, an initial diagnosis of primary cancer of the GI tract is evocated, especially when the time interval from breast cancer diagnosis is long.Histological examination should point towards a metastatic lesion but correct diagnosis can be challenging in some circumstances.One such case relates to signet ring morphology in microscope, where the lesion can be misdiagnosed as primary gastric carcinoma [23,37,[43][44][45]95].Immunohistochemistry is very important in these cases, namely ER and PR antibodies.Another challenging situation is where HR is negative, as it was shown in some of the GI metastases described.The majority of cases of gastric metastases were initially diagnosed as primary gastric tumors (given mainly the presence of signet ring cells).
Upper GI and more precisely stomach was the most common metastatic site.Our analysis confirms previous findings that gastric metastases are associated with the worst prognosis, with survival of no more than 1-1.5 years in most cases [43,95], with only a few exceptions [18,30,37,58,79,94,98].The prognosis of the whole population is in general poor, compared to patients with other metastases such as bone.It should be noted, however, that the follow-up time was generally short and the sample size relatively small, which makes it difficult to draw reliable conclusions about survival.
ILC patients should be treated similarly to IDC patients.Patients with HR-positive and HER2-negative disease should be treated with endocrine therapy.Currently, CDK4/6 inhibitors combined with non-steroidal aromatase inhibitors showed progression-free survival (PFS) benefits against aromatase inhibitor monotherapy and constitute the preferred regimen in the first-line setting.The results of PALOMA-2, MONALEESA-2, and MONARCH-3 trials led to FDA and EMA approval of palbociclib, ribociclib, and abemaciclib respectively [103][104][105].PALOMA-2 trial, in particular, showed significantly improved PFS (HR: 0.58; 95% CI: 0.46-0.72;p < 0.001) in both ILC patients (HR: 0.46) and patients who had visceral metastasis (HR: 0.63), whereas no data about ILC have been reported for ribociclib and abemaciclib [105,106].In addition, prolonged PFS and overall survival (OS) were reported with CDK 4/6 inhibitors in combination with fulvestrant versus fulvestrant monotherapy in the second-line setting [107][108][109].The three available drugs have different adverse events, with neutropenia being the most common dose-limiting toxicity of both ribociclib and palbociclib and diarrhea of abemaciclib.The toxicity profile of each CDK4/6 inhibitor should be considered, especially in patients with GI metastases who have probably already GI symptoms.
Given that patients with gastrointestinal metastases from lobular breast carcinoma should be treated similarly to patients with metastatic breast cancer, early detection of these cases is crucial.Our findings highlight that clinicians (both surgeons and medical oncologists) should be aware of the possibility of GI metastases and obtain a complete and accurate medical history in case of GI tumors, before any treatment decision.Furthermore, in case of medical history of ILC, clinicians should alert pathologists examining GI tumors, as differential diagnosis from primary GI cancers is sometimes challenging.
Our study has certain limitations, primarily its retrospective nature, which is associated with a potential selection bias.In addition, the variability in treatment regimens and treatment modalities does not allow a proper assessment of the optimal treatment.The role of local therapies (surgery, radiation therapy) cannot be further explored in this analysis.

Conclusions
We analyzed the clinical presentation and outcomes of 170 patients with GI metastases from lobular breast carcinoma, most of which had HR-positive, HER2-negative tumors.We conclude that GI metastases are rare and can arise in every part of the GI tract, with the stomach being the common site.Usually, they are initially considered as primary tumors of the GI tract, even if there is a history of breast cancer.A careful histological examination, including specific immunohistochemical biomarkers for breast carcinoma, is the key to the right diagnosis.GI metastases from lobular breast carcinoma should be included in the differential diagnosis of GI lesions and should be managed according to advanced breast cancer algorithms.

TABLE 2 : Characteristics of gastrointestinal metastases.
Symptoms associated with GI metastases did not differ from the ones associated with primary tumors of the GI tract.Therefore, diagnosis of metastatic disease is challenging and purely histological.The most common symptoms were general digestive disorders (46.3%), abdominal pain (23.8%), and bowel obstruction (17.5%).Depending on the exact location of metastasis, other symptoms were also reported, including changes in bowel habits, nausea and vomiting, weight loss, anorexia, dysphagia, anemia, rectorrhagia, jaundice, fatigue, and abdominal mass.In the majority of cases, there was a combination of symptoms.GI metastases appeared simultaneously with other metastases in approximately two-thirds of patients with available data (n=105), whereas 39 patients (37.1%) presented no other metastases.Extra-digestive metastatic locations included the bones (38.1%), peritoneum (19%), lymph nodes (10.5%), ovaries (8.6%), liver (7.6%), brain (6.7%), or other.Surprisingly, the lungs/pleura were only affected in 3.8% of the patients.Nineteen percent of the patients presented with multiple locations involved (Table3).

TABLE 3 : Management of gastrointestinal metastases and outcome.
At least one systemic treatment was given to most of the patients for GI metastatic disease.Among 93 patients with available information on treatment, 83 (89.2%) received systemic therapies for GI metastases, of which 35 patients (37.6%) were treated with successive therapies (hormonal, chemotherapy), 25 (26.9%) with hormonal therapy only, 19 (20.4%) with chemotherapy only, and the rest with other options.Ten patients (10.8%) underwent only surgery, without any systemic treatment.